Using Yoda-1 to mimic laminar flow in vitro: A tool to simplify drug testing
Using Yoda-1 to mimic laminar flow in vitro: A tool to simplify drug testing
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DOI：
10.1016/j.bcp.2019.08.013
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发表时间：
2019-10-01
影响因子：
5.8
通讯作者：
Harper，Matthew T.
中科院分区：
文献类型：
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作者：
Davies，Jessica E.;Lopresto，Dora;Harper，Matthew T.
内皮是一个有吸引力的药物靶点，也是药物不良反应的重要部位。内皮功能障碍与炎症密切相关，并导致药物诱导的心血管毒性。循环中的内皮细胞暴露于血液动力学力，包括剪切应力。包括剪切应力可能会改善未来的内皮细胞药物发现或毒性筛选。Piezo-1是内皮细胞对剪切应力做出反应所必需的。在这项研究中，我们研究了小分子激活剂的压电-1，Yoda-1，是否可以模拟层流诱导的剪切应力对内皮细胞炎症的影响，以及内皮细胞毒性对化疗药物阿霉素的反应。首先，我们测试了Yoda-1是否可以模拟剪切应力对内皮细胞粘附分子ICAM-1和VCAM-1表达的影响。人脐静脉内皮细胞（HUVEC）在静态条件下（有或没有Yoda-1）或在层流诱导的剪切应力（5dyn/cm 2）下培养。Yoda-1和层流具有相似的抗炎作用，降低了TNF-α诱导ICAM-1和VCAM-1表达的能力。然后，我们测试了Yoda-1是否可以模拟剪切应力对多柔比星诱导的细胞毒性的影响。静态培养物的层流和Yoda-1处理增加了阿霉素的细胞毒性。这些发现表明，在静态培养中用Yoda-1激活Piezo-1导致在层流下模拟内皮细胞的内皮细胞表型。Piezo-1的药理学激活可能是模拟静态培养物中恒定剪切应力的有用方法，这可能会改善内皮药物发现和毒性测试。
The endothelium is an attractive drug target and an important site of adverse drug reactions. Endothelial dysfunction is strongly associated with inflammation and contributes to drug-induced cardiovascular toxicity. Endothelial cells in the circulation are exposed to haemodynamic forces including shear stress. Including shear stress may improve future endothelial cell drug discovery or toxicity screening. Piezo-1 is required for endothelial cells to respond to shear stress. In this study, we investigated whether a small molecule activator of Piezo-1, Yoda-1, can mimic the effect of laminar flow-induced shear stress on endothelial cell inflammation, and endothelial cytotoxicity in response to the chemotherapy agent, doxorubicin.First, we tested whether Yoda-1 could mimic the effects of shear stress of expression of the endothelial adhesion molecules, ICAM-1 and VCAM-1. Human umbilical vein endothelial cells (HUVEC) were cultured in static conditions (with or without Yoda-1) or under laminar flow-induced shear stress (5 dyn/cm2). Yoda-1 and laminar flow had similar anti-inflammatory effects, reducing the ability of TNF-α to induce ICAM-1 and VCAM-1 expression. We then tested whether Yoda-1 could mimic the effect of shear stress on doxorubicin-induced cytotoxicity. Both laminar flow and Yoda-1 treatment of static cultures increased the cytotoxicity of doxorubicin. These findings show that Piezo-1 activation with Yoda-1 in static culture leads to an endothelial cell phenotype that mimics endothelial cells under laminar flow. Pharmacological activation of Piezo-1 may be a useful approach to mimic constant shear stress in static cultures, which may improve endothelial drug discovery and toxicity testing.